11 Site Isolation Organic Synthesis in Polystyrene Networks Warren T. Ford
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Department of Chemistry, Oklahoma State University, Stillwater, OK 74078
Reagents supported in solvent-swollen, cross-linked polystyrenes are less mobile than reagents in solution. As a result, the rate of reaction between two polymer-supported species can be retarded relative to the rate of reaction of a polymer-supported species with a soluble reagent or with itself. With 2-10% cross-linked polystyrenes in swelling solvents, reduced mobility provides 1-10 minute lifetimes of polymer-supported reactive intermediates such as an ester enolate, a benzyne, and a glycine active ester. Trapping of the reactive intermediate in less than the lifetime gives kinetically effective site isolation synthesis on a polymer support. Polymer chain mobility decreases with decreased swelling, increased cross-linking, and decreased temperature. Organometallic catalysts can be effectively site isolated by low coverage on the surface of a highly cross-linked macroporous polymer. Within a polymer gel, amine and phosphine ligands provide equilibria between supported organometallic complexes, catalytic activities, and selective reactions different from those in solution. Polymers often have been called immobilizing media for chemical reactions, yet reagents and catalysts bound to solvent-swollen polymers have substantial motional freedom. This is not a contradiction. There would be far fewer misunderstandings about the nature of polymer supports used for reagents and catalysts in organic synthesis if the supports were always called gels, not solids, and if the functional groups were described as being "in", not "on", the polymer. Motion of reagents and catalysts bound into polymer gels is slower than the motion of the analogous reagents and catalysts in solution. Reduced mobility can have dramatic effects on the courses of chemical reactions. This chapter reviews the evidence for, and the consequences of, restricted motion of polymeric reagents. The idea that a polymer support could help to isolate polymer-bound reactive species from one another was suggested and illustrated shortly after the first solid phase peptide syntheses. Cyclic tetrapeptides were obtained in higher yields from polymer-bound 2-nitrophenyl esters than from analogous micromolecular active esters (Scheme 1) (1). Polymer-bound ester enolates were formed at 0 °C and trapped with alkyl bromides and carboxylic acid chlorides with no competing selfcondensation (Scheme 2) (2). Soluble analogs gave primarily self-condensation. 0097-6156/86/0308-0247$10.75/0 © 1986 American Chemical Society
In Polymeric Reagents and Catalysts; Ford, W.; ACS Symposium Series; American Chemical Society: Washington, DC, 1986.
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P O L Y M E R I C R E A G E N T S A N D CATALYSTS
Downloaded by YORK UNIV on October 20, 2014 | http://pubs.acs.org Publication Date: May 5, 1986 | doi: 10.1021/bk-1986-0308.ch011
Scheme 1
The success of both peptide cyclizations and ester enolate trapping is due to the lesser mobility of polymer-bound species, which reduces the rates of the bimolecular reactions that lead to higher oligomeric peptides or to ester self-condensation. Early successes in use of polymer supports as immobilizing media led to optimistic predictions about the future of the synthetic technique of "site isolation on" a polymer support. Failures of the site isolation method soon were discovered. Dieckmann cyclization of polymer-bound diesters gave acceptable yields of six-membered B-keto esters, but valiant attempts to synthesize the nine-membered B-keto ester failed (Equation 1) (2*4). (Zero yield was found also in attempted high dilution Dieckmann cyclization to the nine membered ring in solution (5).) The Dieckmann cyclization results led to a pessimistic review (6) of the potential of site isolation synthesis in polymer gels, which has discouraged further research.
(1)
Kinetic investigations of the lifetimes of polymer-bound benzyne (7.8) and of an N-deprotected amino acid active ester (2) put the concept of site isolation into proper perspective. Polymer-bound reactive intermediates have substantially longer lifetimes than the analogous micromolecular species, but they are not completely isolated, and in time react with other polymer-bound species. Several reviews summarize the field as of 1978-82 (10-17).
In Polymeric Reagents and Catalysts; Ford, W.; ACS Symposium Series; American Chemical Society: Washington, DC, 1986.
11.
Site Isolation Organic Synthesis in Polystyrene Networks
FORD
Downloaded by YORK UNIV on October 20, 2014 | http://pubs.acs.org Publication Date: May 5, 1986 | doi: 10.1021/bk-1986-0308.ch011
Scheme 2
C0C1
^
(PhCH CH ) C0 2
2
2
acylation
PhCH CH CO-Ar 2
2
In Polymeric Reagents and Catalysts; Ford, W.; ACS Symposium Series; American Chemical Society: Washington, DC, 1986.
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250
POLYMERIC R E A G E N T S A N D CATALYSTS
This review emphasizes more recent results and selects earlier work to illustrate specific points. Most research on polymeric reagents has used 1-2% cross-linked polystyrenes that are quite mobile when solvent-swollen. The mobility of polymerbound reactive groups depends critically on the distribution of those groups within the network and on the surface, the chemical nature of the network, the degree of cross-linking, and the swelling solvent. Often those factors have not been investigated, even in attempts at site isolation syntheses, yet they can be manipulated to provide either enhanced site isolation or enhanced cooperation between polymerbound functional groups.
Downloaded by YORK UNIV on October 20, 2014 | http://pubs.acs.org Publication Date: May 5, 1986 | doi: 10.1021/bk-1986-0308.ch011
General Considerations of Reactivity within Polymer Networks Notation. Throughout this chapter the degree of functionalization of polystyrene is reported as DF, the fraction of rings substituted. The % yield of a transformation on a polymer is 100 x DF(product)/DF(reactant). The % cross-linking of a polystyrene is reported as wt % divinylbenzene (DVB) in the monomer mix at the start of copolymerization. Technical D V B typically contains 55% active D V B (meta and para) and 45% ethylvinylbenzenes. Thus a 2% cross-linked polystyrene also contains 1.6% ethylvinylbenzene. Circled P is used for polystyrene, either all para or mixed meta and para isomers. D F = degree of functionalization % cross-linking = wt % divinylbenzene
Polymer Heterogeneity. The microstructures of all common polymer networks are heterogeneous. Copolymerization of styrene (M ) and divinylbenzene (M ) incorporates the first double bond of p-divinylbenzene (r = 0.30, r = 1.02) into the copolymer much faster than styrene, and the first double bond of w-divinylbenzene (r = 0.62, r = 0.54) at about the same rate as styrene (IS). The polymer formed early in a high conversion copolymerization is more highly cross-linked with pdivinylbenzene than the polymer formed late. If a polymer-supported reagent is synthesized via copolymerization of a functional monomer with styrene and divinylbenzene, copolymer reactivity may concentrate the functional groups in the more highly cross-linked regions (p-styryldiphenylphosphine, for example), or in the less cross-linked regions, or they may be nearly randomly distributed throughout the network (w- and p-chloromethylstyrene, for example). Even functional groups incorporated randomly by copolymerization are not in identical environments (IS). Within a single main polymer chain, some are closer to cross-links than others, and some are closer to like functional groups than others. In an atactic vinyl polymer there are many different stereochemical environments. x
2
x
t
2
2
In Polymeric Reagents and Catalysts; Ford, W.; ACS Symposium Series; American Chemical Society: Washington, DC, 1986.
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Site Isolation Organic Synthesis in Polystyrene Networks
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Downloaded by YORK UNIV on October 20, 2014 | http://pubs.acs.org Publication Date: May 5, 1986 | doi: 10.1021/bk-1986-0308.ch011
Microstructural heterogeneity of functional groups can have profound effects on their reactivity (2Q). Reactions of functional groups in polymer networks with large excesses of external reagents commonly follow pseudo first order kinetics to partial conversion, but slow markedly at higher conversion, and often fail to reach completion. Even the most precise kinetics available for a reaction of a cross-linked polymer, in which acetylation by acetic anhydride of 1 mol % of aminostyrene repeat units in a poly(methyl methacrylate) was determined by fluorescence spectroscopy over seven half-lives, gave deviations from first order kinetics with cross-linked polymers but not with soluble polymer (21). The kinetics of reaction of a polymer with a difunctional reagent are still more complex because the degree of cross-linking increases as the reaction proceeds. Macroporous and Microporous Polymers. The common 1-2% cross-linked polystyrenes are microporous, meaning they have no porosity in the dry state. Pores are formed as solvent swells the polymer. They are commonly called gels. "Gel" will be used in this chapter even though the term is slightly misleading, because the network of a macroporous polymer containing solvent is also a gel. During copolymerization of styrene with divinylbenzene in the presence of a solvent, the polymer precipitates as it forms. At high conversion the polymer consists of submicroscopic fused polymer particles and solvent filled pores (22.23). Removal of the solvent leads either to collapse of the network or to permanent pores. Polymers with permanent porosity are called macroporous or macroreticular. The more highly cross-linked the network, and the poorer the solvent used as diluent during polymerization, the more likely the product is to be macroporous. Macroporous polymers appear heterogeneous when viewed with an electron microscope. Their surface areas and average pore sizes can range from 1 |im to >800 m /g and
Cross-linking of Polymers with Difunctional Reagents. Difunctional reagents have been used to produce cross-linked polymers that are more swellable than the standard networks produced by copolymerization with a difunctional monomer, such as divinylbenzene. Alkylation of soluble polystyrene with a,a',-dichloro-p-xylene gives a cross-linked network (Equation 4) that swells even in nonsolvents and has been called "isoporous" (2S). The ease of swelling in nonsolvents is due to the formation of the network in a swollen state (39). The polymer chains in the isoporous network are conformationally relaxed in the swollen state, whereas the polymer chains in a microporous styrene/divinylbenzene network produced by polymerization without solvent are conformationally relaxed in the contracted state. Chloromethylation of polystyrene also produces new cross-links, identified by the conversion of soluble polystyrene to an insoluble polymer and by decreased swelling of chloromethylated polymers compared with the starting polymers (25). Reactions of poly(4-vinylpyridine) (4Q) and of polystyrene (41) with a,0.8) cross-linked polystyrenes with dimethylamine (Equation 5). Small amounts (
